Carbon monoxide: vasoconstrictor or vasodilator? That's the question

Abstract

A STUDY BY BOTROS ET AL. (3) provides evidence that induction of renal heme oxygenase-1 (HO-1) attenuates afferent arterioles (Aff-Art) constrictor responses to increased renal perfusion pressure (RPP), thus suggesting that increased HO-1 modulates renal autoregulation in pathophysiological conditions. The authors elegantly made their conclusions by first showing the HO-1 pattern distribution following heme or SnCl 2 treatment. In particular, the authors demonstrated that in hemin-treated rats HO-1 was expressed in tubular epithelial cells with prominent staining of proximal tubules, whereas in SnCl 2 -treated rats HO-1 was detected in medullary tubular epithelial cells and few proximal tubular cells. Interestingly, HO-1 was not detected in interlobular arteries or Aff-Art following heme or SnCl 2 treatment (Fig. 1). This first set of experiments is consistent with previous studies suggesting the possibility of pharmacologically regulating HO-1 expression and HO activity in a site-specific manner along different nephron segments (1, 18). The authors then examined the physiological significance of such upregulation on Aff-Art constrictor responses to increased RPP. This evidence is of great physiological significance since this strategy has been employed to regulate vascular response in different pathological models such as hypertension (4) or diabetes (6). Additional evidence was provided by more sophisticated experiments employing HO-1 gene transfer by viral agents driven by specific promoters (15). The authors further confirmed this hypothesis showing that HO inhibition by its competitive inhibitor CrMP reversed the effects of heme and SnCl 2 (Fig. 1). This observation led the authors to hypothesize that pharmacological upregulation of HO activity could somehow be related to Aff-Art constrictor responses. To solve this issue, preparations were obtained following treatment with the two by-products of HO activity: carbon monoxide (CO) and biliverdin. In this set of experiments, Botros et al. (3) showed that biliverdin failed to modify Aff-Art autoregulatory responses, whereas superfusing with 1 mmol/l CO results in a significant attenuation of autoregulatory responses to RPP increase (Fig. 1).To better comprehend the authors' conclusions and point out the importance of the present work, one must examine the heme-HO system and its role in the regulation of key elements involved in vascular tone regulation (Fig. 2). Heme is the prosthetic group of numerous enzymes involved in this function, such as soluble guanylate cyclase (sGC) (5), nitric oxide synthase (NOS) (21), cytochrome P-450 (2) and cyclooxygenases (COX) (12). HO is the rate-limiting step in heme degradation, which leads to the formation of CO, biliverdin, and iron. HO exists as the isoenzymes HO-1 (inducible form) and HO-2 (constitutive form) (17). It is well documented that HO-1 is markedly induced by its substrate heme and by heavy metals (17). This fact, in conjunction with the robust ability of HO-1 to regulate blood pressure (18), has stimulated re...

Immunohistochemical expression of fibronectin and C5b-9 in the myocardium in cases of carbon monoxide poisoning

“…Some investigators suggested that CO promotes endothelium-dependent vasoconstriction by inhibiting NO production [28] at vascular level. This is especially true for exogenous CO, as in cases of intoxication [29].…”